1. Field of the Invention
The invention relates to compositions which are EGFR targeting peptides and methods of treating, preventing or managing hyperproliferative cell disease associated with cells expressing EGFR, by administering a delivery vehicle composition comprising an EGFR targeting peptide and a bioactive agent.
2. Background
Epidermal growth factor receptor (EGFR) is a cell surface glycoprotein that is a member of the ErbB family of receptors (reviewed in Yarden Sliwkowski, Nat Rev Mol Cell Biol 2: 127-37, 2001). Activation of EGFR leads to signal transduction cascades that promote cell proliferation and cell growth. Activation is initiated by ligands including epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) binding to the extracellular domain of the receptor. Ligand binding induces conformational changes in EGFR that allow the receptor to homodimerize or to heterodimerize with other ErbB family members such as ErbB2 (HER2). Recent structural studies (Garrett et al., Cell 110: 763-73, 2002; Ogiso et al., Cell 110: 775-87, 2002; Ferguson et al., Mol Cell 11: 507-17, 2003; Hubbard, Cancer Cell 7: 287-8, 2005) have elucidated the molecular details of these conformational changes, demonstrating that the protein shifts from a tethered form, which binds ligand with low affinity and in which the dimerization region of the receptor is masked by intramonomer interactions, to an untethered form, which binds ligand with high affinity and in which the dimerization region is exposed and available for interaction with an additional monomer. Dimerization leads to internalization of the receptor and cell signaling stimulating cell proliferation.
Aberrant EGFR signaling has been implicated in tumor growth and progression (reviewed in Baselga et al., 28, 2000). Studies showed that overexpression of EGFR can lead to cell transformation in culture. Subsequently, numerous tumor types including colon, prostate, non-small cell lung, and breast cancer have been found to overexpress EGFR. EGFR overexpression is associated with poor clinical outcome, including non-responsiveness to chemotherapy, poor prognosis, metastasis, and reduced patient survival. Overexpression of EGFR-binding ligands often accompanies EGFR overexpression, suggesting that autocrine signaling through EGFR is important for cancer progression.
Anti-EGFR agents currently in development or on the market include anti-EGFR antibodies and tyrosine kinase inhibitors. Anti-EGFR antibodies, cetuximab (Goldstein et al., Clin Cancer Res 1: 1311-8, 1995; WO9640210) and panitumumab (U.S. Pat. No. 6,235,883) bind to the receptor ectodomain and prevent ligand binding, thereby attenuating dimerization and inhibiting EGFR signaling. In contrast, the kinase inhibitors such as erlotinib and gefinitib (Traxler, Expert Opin Ther Targets 7: 215-34, 2003) bind to the ATP-binding site of the catalytic domain of the receptor and inhibit signaling by blocking intracellular kinase phosphorylation activity. EGFR signal blocking agents have demonstrated clinical activity. However, while many tumors express EGFR, not all tumor growth is dependent on EGFR cascades. Thus, EGFR overexpression can serve as a cancer marker independently of its role in tumor growth.
The latter principle has been the basis for efforts to use EGFR binding antibody conjugates of cytoxins or anti-EGFR antibody fragments to selectively target liposomal drug formulations. While antibody binding fragments have unique specificity and high affinity for their target, they are large, usually heterodimeric structures, best produced by recombinant protein expression systems. Thus, there is a need in the art for easily manipulated, robust EGFR binding moieties with good specificity and affinity amenable to large scale synthetic production.